Development of New Method for Construction of Chiral, Non-Racemic Quaternary Carbon Center by Enzymatic Acylation of Alcohols and Application Thereof

通过酶催化酰化醇类化合物构建手性非外消旋季碳中心是一种环境友好的方法，具有高的对映选择性和安全性，但成功的实例并不多。这主要是由于目前使用乙烯基酯的最佳方法的问题，其涉及酶的失活和通过分子内酰基迁移容易外消旋化。最近，我们已经公开了他们的决议，通过使用1-乙氧基乙烯基酯（EVE），导致发现的第一个有效的酶解对称的对称二醇和第一个多米诺不对称反应。该项目旨在扩展这些方法用于构建手性，非外消旋季碳中心，以及它们在新药发现的领先化合物的不对称合成中的应用。主要研究结果如下：1.采用酶法去对称化方法， ...更多信息 对1，2-和1，3-二醇都是有效的，并建立了一种新的手性非外消旋季碳中心的通用构建方法。该方法成功地应用于抗肿瘤抗生素fredericamycin A的ABCDE类似物的对映体的不对称合成，以及在C-3位具有手性非外消旋季碳中心和各种N-1保护基的各种羟吲哚（86- 98%ee）的不对称制备.将脂肪酶催化的多米诺不对称合成应用于不同的糠醇，以提供具有手性季碳中心的7-氧杂双环庚烯（91- 99%ee）的一锅合成。特别地，从3-溴糠醇制备了有用的带有溴乙烯基部分的手性配体。第一个涉及动态动力学拆分的多米诺过程是通过α-羟基硝酮的类似反应实现的，以良好的产率得到氮杂多环产物。以易得的外消旋羟基硝酮和马来酸为原料，经3步不对称全合成了天然吡咯里西啶生物碱迷迭香碱。少

Construction of chiral, non-racemic quaternary carbon center via enzymatic acylation of alcohols is believed to be an effective environmentally benign process because of its high enantioselectiviry and safe and easy operation; however, the successful examples have been limited. This is mainly due to the problems of the currently-best method using vinyl esters, which involve inactivation of the enzymes and easy racemication via intramolecular acyl group migration. Recently, we have disclosed their resolution by using 1-ethoxyvinyl esters (EVEs), leading to the discovery of the first effective enzymatic desymmetrization of symmetric diols and the first domino asymmetric reactions. This project has aimed at the expansion of these methods for the construction of chiral, non-racemic quaternary carbon centers and also their application for asymmetric synthesis of leading compounds for new drug discovery. The followings are summary of the results:1. The enzymatic desymmetrization method was e … More ffective for wide range of 1,2- and 1,3-diols, and a new general method for the construcntion of chiral, non-racemic quaternary carbon centers has been established. This protocol was successfully applied for asymmetric synthesis of either enantiomer of the ABCDE-analog of antitumor antibiotic fredericamycin A and also for asymmetric preparation of the various oxindoles (86- 98% ee) with a chiral, non-racemic quaternary carbon center at the C-3 position and a variety of N-1 protective group.2. The lipase-catalyzed domino asymmetric synthesis was applied to various furfuryl alcohol to provide a one-pot synthesis of 7-oxabicycloheptenes (91- 99% ee) with a chiral quaternary carbon center. Especially, useful chiral synthons bearing a vinyl bromide moiety were prepared from the 3-bromofurfuryl alcohols. The first domino process involving dynamic kinetic resolution was achieved by the similar reaction of α-hydroxynitrones to give aza-polycyclic products in good yields. The asymmetric total synthesis of a natural pyrrolizidine alkaloid, rosmarinecine, was attained in 3 steps from a readily available racemic hydroxynitrone and a maleic acid. Less